Skeletal muscle atrophy is characteristic of starvation and a common effect of aging. It is also a nearly universal consequence of severe human illnesses, including cancer, chronic renal failure, congestive heart failure, chronic respiratory disease, insulin deficiency, acute critical illness, chronic infections such as HIV/AIDS, muscle denervation, and many other medical and surgical conditions that limit muscle use. However, medical therapies to prevent or reverse skeletal muscle atrophy in human patients do not exist. As a result, millions of individuals suffer sequelae of muscle atrophy, including weakness, falls, fractures, opportunistic respiratory infections, and loss of independence. The burden that skeletal muscle atrophy places on individuals, their families, and society in general, is tremendous.
The pathogenesis of skeletal muscle atrophy is not well understood. Nevertheless, important advances have been made. For example, it has been described previously that insulin/IGF1 signaling promotes muscle hypertrophy and inhibits muscle atrophy, but is reduced by atrophy-inducing stresses such as fasting or muscle denervation (Bodine S C, et al. (2001) Nat Cell Biol 3(11):1014-1019; Sandri M, et al. (2004) Cell 117(3):399-4121; Stitt T N, et al. (2004) Mol Cell 14(3):395-403; Hu Z, et al. (2009) The Journal of clinical investigation 119(10):3059-3069; Dobrowolny G, et al. (2005) The Journal of cell biology 168(2):193-199; Kandarian S C & Jackman R W (2006) Muscle & nerve 33(2):155-165; Hirose M, et al. (2001) Metabolism: clinical and experimental 50(2):216-222; Pallafacchina G, et al. (2002) Proceedings of the National Academy of Sciences of the United States of America 99(14):9213-9218). The hypertrophic and anti-atrophic effects of insulin/IGF1 signaling are mediated at least in part through increased activity of phosphoinositide 3-kinase (PI3K) and its downstream effectors, including Akt and mammalian target of rapamycin complex 1 (mTORC1) Sandri M (2008) Physiology (Bethesda) 23:160-170; Glass D J (2005) The international journal of biochemistry & cell biology 37(10): 1974-1984).
Another important advance came from microarray studies of atrophying rodent muscle (Lecker S H, et al. (2004) Faseb J 18(1):39-51; Sacheck J M, et al. (2007) Faseb J 21(1):140-155; Jagoe R T, et al. Faseb J 16(13):1697-1712). Those studies showed that several seemingly disparate atrophy-inducing stresses (including fasting, muscle denervation and severe systemic illness) generated many common changes in skeletal muscle mRNA expression. Some of those atrophy-associated changes promote muscle atrophy in mice; these include induction of the mRNAs encoding atroginI/MAFbx and MuRF1 (two E3 ubiquitin ligases that catalyze proteolytic events), and repression of the mRNA encoding PGC-1 α (a transcriptional co-activator that inhibits muscle atrophy) (Sandri M, et al. (2006) Proceedings of the National Academy of Sciences of the United States of America 103 (44): 16260-16265; Wenz T, et al. Proceedings of the National Academy of Sciences of the United States of America 106(48):20405-20410; Bodine S C, et al. (2001) Science (New York, N.Y. 294(5547):1704-1708; Lagirand-Cantaloube J, et al. (2008) The EMBO journal 27(8):1266-1276; Cohen S, et al. (2009) The Journal of cell biology 185(6):1083-1095; Adams V, et al. (2008) Journal of molecular biology 384(1):48-59). However, the roles of many other mRNAs that are increased or decreased in atrophying rodent muscle are not yet defined. Data on the mechanisms of human muscle atrophy are even more limited, although atrogin-1 and MuRF1 are likely to be involved (Leger B, et al. (2006) Faseb J 20(3):583-585; Doucet M, et al. (2007) American journal of respiratory and critical care medicine 176(3):261-269; Levine S, et al. (2008) The New England journal of medicine 358(13):1327-1335). It is therefore beneficial to have compounds that can increase skeletal muscle, muscle hypertrophy. Therefore, compounds that can promote muscle hypertrophy are desired.
Furthermore, it is well known that obesity is a major problem in today's society. Millions of dollars are spent each year in treating diseases directly linked to people being over weight. These problems can be caused by a high adiposity. Therefore, compounds that can decrease adiposity are desired.
Tomatidine is a naturally occurring steroidal alkaloid that is the aglycone form of α-tomatine, an abundant glycoalkaloid in tomato plants and tomatoes. In tomatoes, α-tomatine mediates plant defense against fungi, bacteria, viruses and predatory insects (Koh E et al. (2013) J Sci. Food Agric. 93: 1537-1542). When consumed by animals, α-tomatine is hydrolyzed by stomach acid and intestinal bacteria to tomatidine, which is absorbed by the gut (Friedman M et al (2003) Food Chem. Toxicol. 41: 61-71). Tomatidine appears to have a favorable safety profile based on several studies: 1) human consumption of indigenous variants of tomatoes with very high concentrations of □α-tomatine (up to 0.05% (w/w) of dry tomato weight) appears to cause no adverse effects (Koh E et al. (2013) 1 Sci. FoodAgric. 93: 1537-1542; Rick C et al. (1994) Proc. Natl. Acad. Sci. U.S.A. 91: 12877-12881); 2 α-tomatine content is twice as high in organically grown tomatoes compared to conventionally grown tomatoes (Koh E et al. (2013) J Sci. Food Agric. 93: 1537-1542); and 3) in pregnant and non-pregant mice, dietary supplementation with 0.1% (w/w) tomatidine produces no adverse effects (Friedman M et al (2003) Food Chem. Toxicol. 41: 61-71). Moreover, in mouse models, tomatidine possesses anti-hyperlipidemic and anti-atherosclerotic effects without evidence of toxicity (Fujiwara Y et al. (2012) J. Agric. Food Chem. 60: 2472-2479). Prior to this research, the ability of tomatidine to promote skeletal muscle hypertrophy, increase muscle strength, increase exercise capacity, and decrease adiposity was unknown.
Despite advances in understanding the physiology and pathophysiology of muscle atrophy, there is still a scarcity of compounds that are both potent, efficacious, and selective modulators of muscle growth and also effective in the treatment of muscle atrophy associated and diseases in which the muscle atrophy or the need to increase muscle mass is involved. There is also a need for compounds that can decrease adiposity. There is also a need for compounds that can promote muscle hypertrophy. These needs and other needs are satisfied by the present invention.